The goals of this Program Project are to identify the molecular lesions associated with aggressive clinical behavior of some breast cancers and to translate these molecular insights into prognostic indicators. We will continue our multidisciplinary approach toward understanding the fundamental differences among patients in the cellular biology of the malignant epithelium and its reactive stroma. Three projects will concentrate on the molecular lesions in the tumor cells, while two projects will concentrate on the stroma. Project 1 will evaluate dysregulation of four ETS related transcription factors and their relationship to HER2 oncogene overexpression. Project 2 will clone the target genes of three newly identified amplicons in breast cancer. The next project will evaluate breast cancer molecular cytogenetics using newly developed technologies. Translation to clinically relevant assays will be the responsibility of the Immunopathology Core which will apply discoveries of the Projects to slide-based assays using archival paraffin- embedded tissues. Additional support for the Projects will come from a Clinical Core for tissue accrual, a Biostatistics and Database Core, a Cell Biology Core, and an Administrative Core.